The mechanism of swallowing, also known as deglutition, while generally not given much consideration by healthy individuals, is highly complex and involves the control and coordination of a number of physiologic processes within the body. Initially, food in the mouth is prepared for entry into the esophagus and eventually the stomach and the rest of the gastrointestinal (GI) tract. In the case of solid food, it is chewed, or masticated, and formed into a bolus using the jaw muscles, the teeth, and the tongue. In the case of liquids, the appropriately sized amount of liquid is prepared. Next, the bolus enters the pharynx and subsequently into the esophagus. Peristalsis moves the bolus from the pharynx, through the esophagus, and into the stomach. The swallowing process in the pharynx and the esophagus is coordinated by the autonomic nervous system. Located within the smooth and striated muscle layers of the pharynx and the esophagus are various muscarinic receptors which, although not currently completely understood, when activated, appear to effect peristalsis. These muscarinic receptors help control the smooth and striated muscle layers not only of the esophagus, however, but of the lower gastrointestinal tract, and the bladder. They thus effect peristaltic waves to move materials through the esophagus and the rest of the GI tract and, in the case of the bladder, discharge urine.
Ineffective esophageal motility is associated with many disorders affecting humans. For example, human immunodeficiency virus (HIV) and cancer chemotherapy and radiation patients often have esophageal motility problems related to the disease processes themselves and/or from side effects of treatment. HIV patients, in particular, are currently treated with multi-medication regimens often requiring multiple daily doses. Unfortunately, missing doses of medication can lead to medication resistance in those patients, compromising treatment. In addition, the elderly and patients suffering from strokes or traumatic brain or spinal cord injury, Parkinson's Disease, multiple sclerosis, multiple system atrophy with autonomic phenomena (formerly known as Shy-Drager syndrome), and amyotrophic lateral sclerosis often suffer from ineffective esophageal motility. It has been reported that over one-half of all stroke victims suffer from acute ineffective esophageal motility. It has also been reported that the majority of elderly Parkinson's patients die from bronchial pneumonia and infectious shock and choking is one of the main causes of aspiration pneumonia. Finally, certain drugs can cause such an effect. Examples include antimuscarinics (muscarinic receptor antagonists), including, for example, tolterodine.
Bethanechol, available as 2-carbamoyloxpropyl-trimethyl-amonium chloride, is a parasympathomimetic drug that exerts its effect directly and selectively on the muscarinic M2 receptors and, it is believed, to a certain extent, on the M4 receptors and the M3 receptors and is not inactivated by acetylcholinesterase. See, Liwang L., et at., “Pharmacological discrimination between muscarinic receptor signal transduction cascades with bethanechol chloride.” British Journal of Pharmacology, 138 (2003) 1259-70, incorporated herein by reference, Bethanechol has been used for some time for the treatment of urinary retention associated with neurogenic bladder, to stimulate lower gastrointestinal motility, and to help prevent GERD. Formulations of bethanechol consist of either tablets, sublingual tablets, subcutaneous injection, or an oral solution consisting of, for example, bethanechol chloride (5 mg/ml) combined with a suspending vehicle of Ora-Plus® (Paddock Laboratories, Inc., Minneapolis, Minn.) and either Ora-Sweet® (Paddock Labs) or cherry syrup. Recently, in 50 mg oral doses, bethanechol was shown, after 15 and 40 minutes, to improve esophageal motility. See, Agrawal, A., et at., “Bethanechol improves smooth muscle function in patients with severe ineffective esophageal motility.” Journal of Clinical Gastroenterology, 41 (4) (2007) 366-70, incorporated herein by reference. All such dosing is designed to be absorbed into the blood stream to be made available to the muscarinic receptors. When provided systemically, however, bethanechol can cause undesirable side effects, including diarrhea, flushing, increased sweating, nausea, stomach pain, or gas, and, importantly, urinary urgency. In the case of HIV and cancer chemotherapy patients, moreover, since nutrient absorption is important in treating these patients, the side effects of diarrhea and abdominal cramping precludes the systemic application of bethanechol for esophageal motility problems in these patients. In fact, there is currently no safe and effective treatment for esophageal motility disorders in these patients. Thus, there exists a need for a formulation and method for effectively treating ineffective esophageal motility while eliminating or reducing undesirable side effects associated with systemic dosing.